Inosine monophosphate dehydrogenase (IMPDH) is the rate-limiting enzyme in the de novo biosynthesis of guanosine nucleotides in mammals. Both T- and B-lymphocytes rely exclusively on de novo guanosine nucleotide synthesis, as they are deficient in salvage pathways.
Mycophenolic acid (“MPA”) is a potent inhibitor of IMPDH that has gained widespread acceptance as an immunosuppressant, particularly in the prophylactic treatment of organ rejection in patients receiving allogenic renal, cardiac or hepatic transplants. MPA treatment in the form of the 2-morpholinoethyl ester prodrug mycophenolate mofetil (“MMF”; structure illustrated below) is marketed in the U.S. for these indications by Hoffman LaRoche under the tradename CellCept®:

CellCept® is currently available in capsule (250 mg), tablet (250 mg and 500 mg), oral suspension (200 mg/ml when constituted), and intravenous (6 mg/ml in 5% dextrose when reconstituted) dosage forms. Following oral or intravenous administration, the MMF is rapidly and completely metabolized to the active metabolite MPA (see, e.g., Physicians Desk Reference, 2005 Ed., pp. 2855; “PDR”).
A delayed-release, enterically coated tablet formulation of the sodium salt of mycophenolic acid (mycophenolate sodium) is marketed in the U.S. by Novartis AG under the tradename Myfortic®. Each tablet contains either 180 mg or 360 mg of mycophenolate sodium. According to the 2005 Edition of the PDR, Myfortic® is currently approved for the prophylactic treatment of organ rejection in patients receiving allogenic renal transplants.
The recommended dose of CellCept® is 1 g administered orally or intravenously twice daily for renal transplant (i.e., a daily dose of 2 g; corresponding to a daily dose in the range of about 20-45 mg/kg for a patient body mass in the range of 45-100 kg) and 1.5 g administered orally or intravenously twice daily for hepatic and cardiac transplant (i.e., a daily dose of 3 g; corresponding to a daily dose of about 30-67 mg/kg for a patient body mass in the range of 45-100 kg). The recommended dose of Myfortic® is 720 mg administered orally twice daily (i.e., a daily dose of 1.44 g; corresponding to a daily dose in the range of about 14 mg/kg-32 mg/kg for a patient body mass in the range of 45-100 kg). These relatively large doses are required because clinical evidence does not support their effectiveness to prevent transplant rejection at lower doses. These standard doses require that tablets be of inordinate size so that a patient may consume a minimum number. For MMF, the minimum size tablet approved is 250 mg, with 500 mg being the commonly prescribed tablet. For MPA, the minimum size tablet approved is 180 mg.
Efforts to identify other indications for MMF and MPA have met with limited success to date. Treatment of diabetic nephropathy employing a combination therapy of an ACE inhibitor (Lisinopril; S-1-[N2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-proline dehydrate) and MMF at a dose of 1 g/day (10-22 mg/kg/day depending on patient body mass) has been proposed (PCT publication WO 04/98587). Romero et al., 2000, Atherosclerosis 152:127-133, provided evidence that MMF administered to rabbits at 30 mg/kg/day ameliorated the atherogenic potential of a high-cholesterol diet. This work followed Schreiber et al., 1998, Transpl. Proc. 30:901-902, which studied the effect of MMF at 80 mg/kg (subcutaneous injection) in a similar model. Neither of these indications have received approval from regulatory agencies.
A need exists to identify improved therapeutic compositions and methods that can be used for the therapeutic and/or prophylactic treatment of vascular, autoimmune, and/or inflammatory diseases. The instant disclosure provides such compositions and methods, relying on a novel understanding of IMPDH inhibitors and their utility in treating certain vascular, autoimmune and/or inflammatory disease processes.